Anhedonia has been one of the two key diagnostic criteria for major depressive disorder (MDD) since the publication of The Diagnostic and Statistical Manual of Mental Disorders, Third Edition, yet little is known about its neural substrates. Neuroimaging studies have identified numerous brain regions that are thought to be involved with MDD. Most studies dealt with MDD as a syndromal entity, and not surprisingly, yielded quite variable results with respect to the areas of the brain identified, the nature of the functional changes (i.e., decrease or increase in activities), lateralization, and correlation with clinical symptoms. Clinical heterogeneity and lack of symptom-specific targets are presumably among the factors contributing to the variability. The hypothesis that a functionally impaired mesolimbic dopaminergic pathway may comprise a part of neural substrate underlying core MDD symptoms of anhedonia and loss of motivation has been proposed. Nevertheless, the roles of brain reward mechanisms in mediating anhedonia in MDD remain unclear. Availability of appropriate experimental paradigms that can be used empirically to measure anhedonia is a prerequisite to test such a hypothesis. Recent studies using monetary incentive paradigms coupled with neuroimaging techniques have identified hemodynamic responses in structures that serve as part of the mesolimbic dopaminergic pathway during processing rewards in healthy humans. We hypothesize that anhedonia in MDD is associated with impairment of brain reward mechanisms such that dysfunction of the orbital and ventromedial frontal cortices involved in the impaired hedonic attribution capacity, while dysfunction of the ventral striatum area that contains the nucleus accumbens is involved with the reduced or lack of reactivity to rewarding environmental stimuli in patients with MDD. Our hypothesis is postulated to link specific neural substrates to the two psychiatric components of anhedonia, i.e., loss of interest and lack of reactivity, as defined in the diagnostic criteria for MDD. We plan to operationally test our hypothesis by using empirical measurement of reward responses in MDD patients with and without significant anhedonia using a monetary incentive event-related functional magnetic resonance imaging task recently developed at NIH. We expect to find reduced activation of the ventral striatum, orbital and ventromedial frontal cortices in response to monetary incentive stimuli in MDD patients with significant anhedonia relative to MDD patients without anhedonia and healthy control. The outcome of the proposed work may provide clues for diagnosis, classification, and treatment of MDD, and may also yield leads for identifying the fundamental neural mechanisms underlying anhedonia in other disabling psychiatric conditions such as schizophrenia and addiction. This project was initiated during Summer of 2003 and although several subjects have been entered, no results are yet available.